Developmental profile of GABAA-receptors in the marmoset monkey: Expression of distinct subtypes in pre- and postnatal brain

Gamma aminobutyric acid (GABA)_A-receptors are expressed in fetal mammalian brain before the onset of synaptic inhibition, suggesting their involvement in brain development. In this study, we have analyzed the maturation of the GABA_A-receptor in the marmoset monkey forebrain to determine whether distinct receptor subtypes are expressed at particular stages of pre- and postnatal ontogeny. The distribution of the subunits α1, α2, and β2,3 was investigated immunohistochemically between embryonic day 100 (6 weeks before birth) and adulthood. Prenatally, the α2- and β2,3-subunit-immunoreactivity (-IR) was prominent throughout the forebrain, whereas the α1-subunit-IR appeared in selected regions shortly before birth. The α2-subunit-IR disappeared gradually to become restricted to a few regions in adult forebrain. By contrast, the α1-subunit-IR increased dramatically after birth and replaced the α2-subunit in the basal forebrain, pallidum, thalamus, and most of the cerebral cortex. Staining for the β2,3-subunits was ubiquitous at every age examined, indicating their association with either the α1- or the α2-subunit in distinct receptor subtypes. In neocortex, the α1-subunit-IR was first located selectively to layers IV and VI of primary somatosensory and visual areas. Postnatally, it increased throughout the cortex, with the adult pattern being established only during the second year. The switch in expression of the α1- and α2-subunits indicates that the subunit composition of major GABA_A-receptor subtypes changes during ontogeny. This change coincides with synaptogenesis, suggesting that the emergence of α1-GABA_A-receptors parallels the formation of inhibitory circuits. A similar pattern has been reported in rat, indicating that the developmental regulation of GABA_A-receptors is conserved across species, possibly including man. However, the marmoset brain is more mature than the rat brain at the onset of α1-subunit expression, suggesting that α1-GABA_A-receptors are largely dispensable in utero, but may be required for information processing after birth. © 1996 Wiley-Liss, Inc.     

Redirecting the complete T cell receptor/CD3 signaling machinery towards native antigen via modified T cell receptor

We show that a chimeric T cell receptor (TCR) β chain consisting of a single-chain Fv portion derived from a monoclonal antibody and the full TCR β chain is able to assemble functionally with endogenous TCR/CD3 components and transfer the antibody specificity as well as the TCR specificity into TCRβ⁻ as well as into TCRβ⁺ T cells. This allows the incorporation new non-major histocompatibility complex-restricted ligand specificities into the intact TCR/CD3 complex which can exploit the full range of biological activities of the endogenous TCR signaling machinery. This approach can provide wider opportunities to redirect T cells to virus or tumor antigen-bearing cells.     

Basal asynchrony and resynchronization with biventricular pacing predict long-term improvement of LV function in heart failure patients

Biventricular pacing (BiV) is emerging for patients with dilated cardiomyopathy (DCM) and asynchrony. We measured basal asynchrony and early resynchronization by radionuclide angioscintigraphy (RNA) in order to predict long-term evolution of ventricular function after BiV. Thirty-four patients (NYHA Class III-IV,65.4 +/- 11 years) with large QRS(179 +/- 18 ms)were implanted with BiV and studied by RNA before (D0), at day 8 (D8), and during follow-up(20 +/- 7 months). We calculated left and right ejection fractions, the interventricular dyssynchrony (TRVLV), and the apicobasal dyssynchrony (Tab). LVEF improved from 20.2 +/- 8.1%(D0) to27.1%+/- 12.6%(follow-up,P < 0.003 vs D0) and RVEF from 28.6%+/- 13%(D0) to 34.3 +/- 11.5%(follow-up,P < 0.03 vs D0). Inter- (DeltaTRVLV) and intraventricular resynchronization was immediate and remained stable: TRVLV decreased from 68.3 +/- 38 ms(D0) to 13.4 +/- 48.5 ms(D8) and1.8 +/- 39.2 ms(follow-up,P < 0.0001 vs D0); and Tab from 45.8 +/- 64.1 msto-18 +/- 68(D8) and-28.3 +/- 53.6 ms(follow-up,P < 0.0001 vs D0). Early inter- and intraventricular resynchronization (DeltaTab) at D8 were related to late LVEF and RVEF improvement. Together, an LVEF > 15% and a significant interventricular dyssynchrony (TRVLV > 60 ms) at D0 have a sensitivity of 79% and a positive predictive value of 83% to predict an improvement of LVEF superior to 5% at follow-up. In DCM patients, BiV resynchronizes ventricles early and in the long-term, while RVEF and LVEF improve progressively. Patients with large electromechanical dyssynchrony benefit most from BiV.